Heretofore, proteins that participate in the adhesion of cells to interstitial connective tissues and have various physiological activities relevant to the cellular function of animal cells have been referred to as cell adhesion-activating proteins. As such proteins, for example, known are fibronectin, laminin, vitronectin, etc.
Further, it is known that the core sequence of the cell-bonding site of these proteins is comprised of arginine-glycine-aspartic acid, Arg-Gly-Asp (hereinafter referred to as RGD sequence: see Pierschbachr, M. D. et al, Nature, 309, 30 (1984); Suzuki, S. et al, J. Biol. Chem., 259, 15307 (1984); Plow, E. et al, Proc. Natl. Acad. Sci. USA, 82, 8057 (1985)).
It is-known that fibrinogen existing in plasma interacts with platelet membrane glycoprotein IIb/IIIa complex via the RGD sequence thereby causing aggregation of platelets, and since a synthetic peptide having the RGD sequence inhibits the interaction between fibrinogen and the platelet membrane glycoprotein IIb/IIIa complex, it is considered that such a synthetic peptide will be effective as a platelet aggregation inhibitor (see Phillips, D. R., Cell, 65, 359 (1991)). Further, it is also known that a snake venom-derived peptide having the RGD sequence significantly inhibits the born resorption by osteoclasts (see Sato, Met al, J. Cell Biol., 111, 1713 (1990)).
It is considered that fibronectin participates in the adhesion of cells to interstitial connective tissues and also in differentiation and growth of cells in such a way that it adheres to the receptor of adhesive cells via its RGD sequence while transmitting its information to the cells (see Yamada, K. M., Ann. Rev. Biochem., 52, 761 (1983)).
Since fibronectin stimulates the wandering ability of fibroblasts and macrophages, it is considered that it can be applied to the remedy of wounds and to the control of the function of immunological competence. In particular, the local remedy of corneal disorders with fibronectin by utilizing its wound remedy-promoting effect has already been attempted (see Fujikawa, L. S. et al, Lab. Invest., 45, 120 (1981)). In addition, cell adhesion-activating proteins have been specifically noted as substances that participate in cancer metastasis. During the process of cancer metastasis, cancer cells are brought into contact with various host cells or biopolymers, and it is known that if cell adhesion-activating proteins such as fibronectin and laminin exist in the process, cancer cells form multicellular masses thereby more facilitating the growth and existence of the cancer cells themselves.
On the other hand, it has been confirmed that the adhesive core of fibronectin, tripeptide Arg-Gly-Asp (see Humphries, M. J. et al, Science, 233, 467 (1986) and the adhesive core of laminin, pentapeptide Tyr-Ile-Gly-Ser-Arg (see Iwamoto, Y. et al, Science, 238, 1132 (1987)) inhibit cancer metastasis.
As mentioned above, cell adhesion-activating proteins such as fibrinogen, fibronectin, laminin and others have various physiological activities, and pharmaceutically-active substances that selectively interact with the receptors of such proteins are expected to be applicable to preventives or remedies for various disorders. However, the peptides mentioned above have problems in that their specificity to the receptors and their absorbability and stability in vivo are low.
On the other hand, non-peptidic compounds that interact with the receptors of cell adhesion-activating proteins have been reported, for example, in J. Med. Chem.,35, 4393 (1992), EP 505868, Japanese Patent Laid-Open No. 4-288051, etc. However, none of these that have heretofore been reported is satisfactory for clinical use.
Under-the situation, it has been desired to develop platelet aggregation inhibitors, cancer metastasis inhibitors, wound remedies or bone resorption inhibitors which interact more selectively with cell adhesion-activating proteins such as fibrinogen, fibronectin and others and which have more excellent in vivo absorbability and stability.